Eicosanoid signalling pathways in the heart

Abstract

Myocardial phospholipids serve as primary reservoirs of arachidonic acid (AA), which is liberated through the rate-determining hydrolytic action of cardiac phospholipases A2 (PLA2s). A predominant PLA2 in myocardium is calcium-independent phospholipase A2β (iPLA2β), which, through its calmodulin (CaM) and ATP-binding domains, is regulated by alterations in local cellular Ca2+ concentrations and cardiac bioenergetic status, respectively. Importantly, iPLA2β has been demonstrated to be activated by ischaemia through elevation of the concentration of myocardial fatty acyl-CoA, which abrogates Ca2+/CaM-mediated inhibition of iPLA2β. AA released by PLA2-catalysed hydrolysis of phospholipids serves as a precursor for eicosanoids generated by pathways dependent on cyclooxygenases (COX), lipoxygenases (LOX), and cytochromes P450 (CYP). Eicosanoids initiate and propagate diverse signalling cascades, primarily through their interaction with cellular receptors and ion channels. However, during pathologic states such as ischaemia or congestive heart failure, eicosanoids contribute to multiple maladaptive changes including inflammation, alterations of cellular growth programmes, and activation of multiple transcriptional events leading to the deleterious sequelae of these pathologic states. This review summarizes the central roles of myocardial PLA2s in eicosanoid signalling in the heart, the major COX, LOX, and CYP pathways of eicosanoid generation in the myocardium, and the effects of important eicosanoids on receptor-, ion channel-, and transcription-mediated processes that facilitate cardiac hypertrophy, mediate ischaemic preconditioning, and precipitate arrhythmogenesis in response to pathologic stimuli.